Protective effect of progestin in hormone replacement therapy appears to be dose-related

To help protect against endometrial cancer, women who take estrogen replacement therapy should also take progestin at least 10 days a month, say researchers at the University of Washington. Progestins are hormones that oppose the effects of estrogen on the endometrial cells that line the uterus.

Dr. Shirley Beresford, associate professor of epidemiology, and Dr. Noel Weiss, professor of epidemiology, publish results of their study this Saturday in The Lancet.

Taking estrogen after menopause can significantly reduce women’s risk of heart disease and osteoporosis, but since estrogen stimulates the growth of the endometrial cells, estrogen replacement therapy can also increase the risk of endometrial cancer.

Although endometrial cancer is relatively rare — even with the increased risk associated with estrogen therapy — and although it is usually curable, this side effect is cause for concern. Therefore, many estrogen replacement regimens now include taking a progestin at least several days a month.

To determine how well this strategy works and which dosing regimens are best, the researchers interviewed 832 women who had had endometrial cancer and 1,114 women who had not, about their medical history and use of hormone replacement therapy.

They found that women who took estrogen without also taking progestin had a four-fold increase in risk of endometrial cancer, compared to women who had never taken hormone replacement therapy or had taken it for less than six months.

By contrast, there was only small increase in risk of endometrial cancer in women who took progestin along with their estrogen therapy.

“This apparent protective effect seems to depend a great deal on how many days a month the women took the progestin,” said Beresford. For women who took progestin for 10 days or two weeks a month, there was no statistically increased risk of endometrial cancer. But among those who took progestin for fewer than 10 days a month, the risk was three times higher compared to non-users.

“Women taking the combination therapy should be sure take it for at least 10 days a month,” said Weiss.

While cautioning that their results are preliminary, the researchers also report evidence that the protective effect of progestin may diminish over the long term. They found that even among women who took progestin for 10 days or two weeks a month, those who took the combination therapy for more than five years had a 2.5 times greater risk of endometrial cancer compared to women who had never taken hormones.

“This finding of increased risk associated with long use of estrogen combined with cyclic progestin therapy is new, and needs to be replicated by other investigators,” commented Beresford.

The researchers also noted that their study does not provide information on women who take combined therapy every day of the month.

“The risk of endometrial cancer is small, occurring in less than one woman in a thousand each year,” said Weiss. “Even with hormone replacement therapy, the risk remains small. The cancer is almost always contained in the uterus and is usually curable.”

Co-authors of the study are Lynda Voigt, auxiliary faculty in epidemiology, and Barbara McKnight, professor of biostatistics. The research was funded by grants from the National Cancer Institute.